DESCRIPTION: Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system characterized by progressive loss of cognitive skills and associated with neuropathologic features including amyloid deposits and neurofibrillary tangles. Although the etiology of AD is most likely multifactorial, including environmental factors, some families show a clear pattern of autosomal dominant transmission and such cases are referred to as familial AD (FAD). Recently a gene called S182 or presenilin corresponding to the FAD locus on chromosome 14 was cloned. More than 20 different mutations in this gene have now been identified. The goal of this proposal is to generate an animal model of FAD. The specific aims are: 1. Make a PS1 transgenic animal using PS1 with the rat neuron-specific enolase promotor. A normal PS1 clone, Met146leu, or ala246-glu mutation forms of PS1 will be used. 2. Introduce pro267ser into the endogenous mouse PS1 gene using homologous recombination. 3. A knock-in approach will be used to introduce human PS1 with the glu280ala mutation into exon 3 of the mouse gene. 4. Develop human-specific antibodies.